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Aims Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV).Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a 'fetal gene program' contributing to pathological cardiac remodeling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodeling in response to pressure overload induced by pulmonary artery banding (PAB). Methods and results In the present study, Hand2F/F and MCM- Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived hemodynamic parameters as well as molecular remodeling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV-pressure overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass and impaired cardiac function. RNA sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. Conclusions Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressure overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodeling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure. Translational perspective RV failure associated with pulmonary hypertension reduces long-term survival rate to 55% within 3 years, suggesting that 3 years after diagnosis almost half of the patients will die. To revert these numbers an adequate RV-specific and, therefore, more efficient treatment is needed. Our work suggests that current therapies and potential mechanisms underlying LV failure may not be suitable for RV failure. While Hand2 deletion is favorable in LV response to stress, it is particularly detrimental in the RV under similar conditions, and thus, highlighting potential severe consequences of not differentiating therapeutic targets or treatment for RV or LV failure.

Background: Treatment of patients with pulmonary arterial hypertension (PAH) is conventionally based on functional plus invasive measurements obtained during right heart catheterization (RHC). Whether risk assessment during repeated measurements could also be performed on the basis of imaging parameters is unclear, as a direct comparison of strategies is lacking. Research Question: How does the predictive value of noninvasive parameters compare with that of invasive hemodynamic measurements 1 year after the diagnosis of idiopathic PAH? Study Design and Methods: One hundred and eighteen patients with idiopathic PAH who underwent RHC and cardiac MRI (CMR) were included in this study (median time between baseline evaluation and first parameter measures, 1.0 [0.8-1.2] years). Forty-four patients died or underwent lung transplantation. Forward Cox regression analyses were done to determine the best predictive functional, hemodynamic, and/or imaging model. Patients were classified as high risk if the event occurred < 5 years after diagnosis (n = 24), whereas patients without event were classified as low risk. Results: A prognostic model based on age, sex, and absolute values at follow-up of functional parameters (6-min walk distance) performed well (Akaike information criterion [AIC], 279; concordance, 0.67). Predictive models with only hemodynamic (right atrial pressure, mixed venous oxygen saturation; AIC, 322; concordance, 0.66) or imaging parameters (right ventricular ejection fraction; AIC, 331; concordance, 0.63) at 1 year of follow-up performed similarly. The predictive value improved when functional data were combined with either hemodynamic data (AIC, 268; concordance, 0.69) or imaging data (AIC, 273; concordance, 0.70). A model composed of functional, hemodynamic, and imaging data performed only marginally better (AIC, 266; concordance, 0.69). Finally, changes between baseline and 1-year follow-up were observed for multiple hemodynamic and CMR parameters; only a change in CMR parameters was of prognostic predictive value. Interpretation: At 1 year of follow-up, risk assessment based on CMR is at least equal to risk assessment based on RHC. In this study, only changes in CMR, but not hemodynamic parameters, were of prognostic predictive value during the first year of follow-up.

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [ 11 C]-hydroxyephedrine positron emission tomography ([ 11 C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity. [ 11 C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [ 11 C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [ 11 C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [ 11 C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [ 11 C]HED retention index was lower compared to LV tracer uptake (p

BackgroundPulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA–RV interaction.MethodsPAH patients with low or high end-diastolic elastance (Eed) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying−RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure.ResultsWith increased Eed, RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high Eed, resulting in higher vena cava backflow. Upon treatment, Eed was reduced in ~50% of the patients with high Eed, which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom Eed remained high.ConclusionsIn PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline Eed, diastolic stiffness remained high, despite treatment. A reduction in Eed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.

BACKGROUND: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages. METHODS: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49). RESULTS: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAHpatients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females < 45years had best prognosis in comparison to females & GE;55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females < 45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females < 45years had an event at a later time point, RV function was more impaired at end-stage disease. CONCLUSIONS: Sex hormones are differently associated with RV function in male and female PAHpatients. DHEA-S appeared to be lower in male and female PAH-patients. Females < 45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease.J Heart Lung Transplant 2022;41:445-457 (c) 2021 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Hyperventilation is common in pulmonary arterial hypertension and may be related to autonomic imbalance. Patients underwent exercise testing and hyperoxic breathing before and after bisoprolol treatment. We found that neither beta blocker treatment nor hyperoxic breathing in patients reduced hyperventilation at rest and during exercise, although it reduced heart rate.

Background Drugs approved for pulmonary arterial hypertension have been considered for patients with heart failure with preserved ejection fraction and combined post- and precapillary pulmonary hypertension (Cpc-PH). We aimed to study changes in cardiac volumes, cardiac load and left ventricular (LV) filling pressures in patients with heart failure with preserved ejection fraction and Cpc-PH in response to pulmonary arterial hypertension-specific treatment. Methods and Results In this prospective study, 23 patients with heart failure with preserved ejection fraction and Cpc-PH underwent right-heart catheterization, including acute provocation testing (fluid loading and inhaled nitric oxide) and cardiac MRI at baseline. Right-heart catheterization and cardiac MRI were repeated after 4 months of treatment. At baseline, acutely increasing preload by fluid loading resulted in a significant increase in pulmonary arterial wedge pressure (PAWP), whereas reducing right ventricular (RV) afterload and increasing LV distensability by acute administration of inhaled nitric oxide had no effect on PAWP. After 4 months of treatment, we observed a significant reduction in RV and LV afterload and increased RV and LV stroke volume, but PAWP significantly increased. Conclusions In patients with heart failure with preserved ejection fraction and Cpc-PH, 4 months of pulmonary arterial hypertension-specific treatment increased RV and LV stroke volume at the expense of increased PAWP. This increase in PAWP was similarly observed acutely after fluid loading.

BACKGROUND: Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure.METHODS: Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks.RESULTS: In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function.CONCLUSIONS: Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.

Background Echocardiography is considered the cornerstone of the diagnostic workup of heart failure with preserved ejection fraction. Thus far, validation of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) echo‐algorithm for evaluation of diastolic (dys)function in a patient suspected of heart failure with preserved ejection fraction has been limited. Methods and Results The diagnostic performance of the 2016 ASE/EACVI algorithm was assessed in 204 patients evaluated for unexplained dyspnea or pulmonary hypertension with echocardiogram and right heart catheterization. Invasively measured pulmonary capillary wedge pressure (PCWP) was used as the gold standard. In addition, the diagnostic performance of H 2 FPEF score and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) were evaluated. There was a poor correlation between indexed left atrial volume, E/e′ (septal and average) or early mitral inflow (E), and PCWP ( r =0.25–0.30, P values all r =0.17, P 2 FPEF score had a modest correlation with PCWP ( r =0.44, P r =0.24, P Conclusions The 2016 ASE/EACVI algorithm for the assessment of diastolic function has a limited diagnostic accuracy in patients evaluated for unexplained dyspnea and/or pulmonary hypertension, and especially sensitivity to detect diastolic dysfunction was low.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) are both associated with right ventricular (RV) failure and mortality. However, CTEPH patients are older, more often male and usually have more co-morbidities than iPAH patients, including a history of venous thromboembolism. Therefore, RV adaptation to pressure-overload in CTEPH may be different than in iPAH. Methods: We included all treatment-naive CTEPH and iPAH patients diagnosed in the Amsterdam UMC between 2000 and 2019 if cardiac magnetic resonance imaging (CMR) and a right heart catheterization were performed at time of diagnosis. Load-dependent RV volumes and mass were assessed with CMR. Load-independent RV contractility, afterload and diastolic stiffness in relation to afterload were obtained using single beat pressure-volume loop analysis. Differences in RV characteristics between CTEPH and iPAH were analyzed using multiple linear regression with interaction testing after correcting for confounders. Results: We included 235 patients in this study and performed pressure-volume loop analysis in 136 patients. In addition to being older and more often male, CTEPH patients had a lower pulmonary vascular resistance than iPAH patients at the time of diagnosis. After correcting for these confounders, CTEPH patients had a somewhat higher RV end-diastolic volume index (87 ± 27 ml vs 82 ± 25 ml; p

The search for new biomarkers for right ventricular maladaptation in pulmonary hypertension is exciting. At this moment we are missing some key information that hampers full-scale clinical implementation.https://bit.ly/37xbgwx

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH)) are both associated with right ventricular (RV) failure and death. Although both conditions develop in the pre-capillary pulmonary vasculature, patient characteristics are different. CTEPH patients are older, predominantly male and more often have a history of venous thromboembolism. Therefore, the RV might be affected differently in CTEPH compared to iPAH. We aimed to compare RV adaptation in CTEPH and iPAH. Methods: Between 2000 and 2019 all treatment naive iPAH and CTEPH patients diagnosed in the Amsterdam UMC were included if a right heart catheterization and cardiac magnetic resonance imaging (CMR) were performed at the time of diagnosis. RV volumes, mass and function were assessed with CMR. RV contractility, afterload, RV-pulmonary artery (RV-PA) coupling and diastolic stiffness (Eed) were obtained using single beat pressure-volume loop analysis. Differences in RV phenotypes between iPAH and CTEPH were analyzed using multiple linear regression with interaction testing after correcting for confounders. Results: A total of 235 patients were included, 116 with CTEPH and 119 with iPAH. CTEPH patients were older, predominantly male, had a higher systemic blood pressure and a lower pulmonary vascular resistance at the time of diagnosis. After correcting for these confounders, RV function and RV-PA coupling were similar in both groups. However, CTEPH patients had a higher RV end-diastolic volume index (87±27 ml/m2 vs. 82±25 ml/m2), and a lower RV wall thickness (0,6±0,1 g/ml vs. 0,7±0,2 g/ml; figure 1A). The increase in afterload in CTEPH was associated with a disproportionally larger increase in diastolic stiffness compared to iPAH, independent of RV wall thickness (figure 1B). Conclusions: Despite a similar RV function, the RV in CTEPH is more dilated and stiffer than the RV in iPAH, independent of age, sex and afterload.

Introduction: Newly diagnosed idiopathic pulmonary arterial hypertension (PAH) patients increasingly have features of patients with heart failure with preserved ejection fraction (HFpEF). These so-called “atypical” PAH patients can be identified using the H2FPEF-score (Reddy, Circulation 2018). This patient group is often excluded from clinical trials, and it is therefore unclear whether they respond similarly to PAH-specific medication. Aim: To assess baseline characteristics and treatment response of patients diagnosed with PAH stratified by the H2FPEF-score. Methods: A retrospective analysis of 253 treatment naïve PAH-patients who underwent diagnostic right heart catheterization at baseline. Groups were compared with ANOVA, post-hoc pairwise t-tests with Bonferroni correction and multivariate Cox proportional hazards analysis. Results: This cohort included 58 (23%) patients with a low (≤1), 159 (63%) patients with an intermediate (2-5) and 36 (14%) patients with a high (≥6) H2FPEF-score. Patients with a high H2FPEF-score were older and more often male, used more diuretics, had more comorbidities and had more often PAH with severely impaired diffusion capacity compared to patients with a low H2FPEF-score. In addition, patients with a high H2FPEF-score had a significantly lower cardiac index, mixed venous blood gas, oxygen saturation and 6-minute walk distance (6MWD) compared to patients with a low H2FPEF-score. A high H2FPEF-score was associated with worse survival despite correcting for confounders (HR 2.99, 95% CI 1.53-5.84, Fig.1 A). Despite potential survival bias, at 1-year follow-up 6MWD (Fig.1 B) significantly improved in patients with a low and intermediate H2FPEF-score, but did not change in patients with a high H2FPEF-score (interaction p-value< 0.001). Conclusions: A high H2FPEF-score is associated with worse survival in PAH. Also, no improvement in 6MWD was observed in patients with a high H2FPEF-score only.

BACKGROUND: Pulmonary vascular resistance (PVR) and compliance are comparable in proximal and distal chronic thromboembolic pulmonary hypertension (CTEPH). However, proximal CTEPH is associated with inferior right ventricular (RV) adaptation. Early wave reflection in proximal CTEPH may be responsible for altered RV function. The aims of the study are 1) investigate whether reflected pressure returns sooner in proximal than in distal CTEPH, and 2) elucidate whether timing of reflected pressure is related to RV dimensions, ejection fraction (RVEF), hypertrophy and wall stress.METHODS: Right heart catheterization and cardiac MRI were performed in 17 patients with proximal and 17 patients with distal CTEPH. In addition to determination of PVR, compliance and characteristic impedance, wave separation analysis was performed to determine the magnitude and timing of the peak reflected pressure (as % of systole). Findings were related to RV dimensions and time-resolved RV wall stress.RESULTS: Proximal CTEPH was characterized by higher RV volumes, mass and wall stress, and lower RVEF. While PVR, compliance and characteristic impedance were similar, proximal CTEPH was related to an earlier return of reflected pressure than distal CTEPH (proximal 53±8% vs. distal 63±15%, PCONCLUSIONS: Poor RV function in patients with proximal CTEPH is related to an early return of reflected pressure wave. PVR, compliance and characteristic impedance do not explain differences in RV function between proximal and distal CTEPH.

Background: In recent years, newly diagnosed pulmonary arterial hypertension (PAH) patients have increasing features of patients with heart failure with preserved ejection fraction (HFpEF). A high HFpEF probability, quantified by the H2FPEF-score, may predict treatment response. Objective: To assess whether a high H2FPEF-score predicts treatment response in patients diagnosed with PAH . Methods: A retrospective cohort of 253 idiopathic PAH-patients underwent diagnostic right heart catheterization at baseline and in a subset of patients (n=150) follow-up measurements were available at 1.00 [0.74-1.28] year. Results: This cohort included 55 (22%) patients with a low (≤1), 160 (63%) patients with an intermediate (2-5) and 38 (15%) patients with a high (≥6) H2FPEF-score. Patients with a high H2FPEF-score at time of diagnosis were older, had more comorbidities, a lower DLCO and larger left atrial area compared to patients with a low H2FPEF-score. PAH-specific treatment was comparable among all groups and a similar reduction in PVR at 1-year follow-up was observed. Overall, 6-minute walk test significantly improved after treatment (322±147 to 388±143 m). This improvement was seen in all groups, although only significant in the groups with a low and intermediate H2FPEF-score. No significant correlation was observed between the H2FPEF-score and left atrial area or PCWP. Finally, survival for patients with a high H2FPEF-score was significantly worse than for patients with a low H2FPEF-score. Conclusion: A high H2FPEF-score does not predict hemodynamic or exercise response to vasodilator treatment in PAH, but is nonetheless associated with increased mortality.

Aims: Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Methods and results: Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Conclusion: Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.

BACKGROUND: Between 16% and 51% of patients with chronic thromboembolic pulmonary hypertension will have residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). Whether residual PH is related to remaining (sub-)segmental macrovascular lesions or to microvascular disease is unknown. New imaging techniques can provide detailed information about (sub-)segmental pulmonary arteries and parenchymal perfusion. The aim of this study was to describe the prevalence after PEA of remaining (sub-)segmental vascular lesions on electrocardiogram-gated computed tomography pulmonary angiography (CTPA) and parenchymal hypoperfusion on magnetic resonance imaging (MRI) and to relate these imaging abnormalities to the presence or absence of residual PH after PEA.METHODS: In a prospective cohort of patients with operable chronic thromboembolic pulmonary hypertension, hemodynamics, CTPA, and lung perfusion MRI were performed before and 6 months after PEA. The percentage of (sub-)segmental vascular lesions was calculated on CTPA and parenchymal hypoperfusion on lung perfusion MRI.RESULTS: PEA led to significant improvements in hemodynamics and a reduction of imaging abnormalities. Residual PH was present in 45% of patients after PEA, whereas remaining (sub-)segmental vascular lesions and parenchymal hypoperfusion were present in 20% and 21% of the pulmonary vasculature, respectively. Patients with and without residual PH after PEA had similar percentages of remaining (sub-)segmental vascular lesions (25% +/- 14% vs 17% +/- 15%; p = 0.16) and similar degrees of parenchymal hypoperfusion (20% +/- 7% vs 19% +/- 6%; p = 0.63).CONCLUSIONS: After successful PEA, advanced imaging shows that around 20% of the pulmonary vasculature remains abnormal, independent of the presence of residual PH. This may suggest that microvascular disease, rather than residual macrovascular lesions, plays a prominent role in residual PH after PEA. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved.

Vena cava backflow is a well-recognised clinical hallmark of right ventricular failure in pulmonary arterial hypertension (PAH). Backflow may result from tricuspid regurgitation during right ventricular systole or from impaired right ventricular diastolic filling during atrial contraction. Our aim was to quantify the forward and backward flow in the vena cava and to establish the main cause in PAH.In 62 PAH patients, cardiac magnetic resonance measurements provided volumetric flows (mL·s−1) in the superior and inferior vena cava; time integration of flow gave volume. The “backward fraction” was defined as the ratio of the backward and forward volumes in the vena cava, expressed as a percentage. Time of maximum vena cava backflow was expressed as a percentage of the cardiac cycle. Right ventricular volumes and aortic stroke volume were determined. Right heart catheterisation gave right ventricular and right atrial pressures. Right ventricular end-diastolic stiffness was determined with the single-beat method.The median (interquartile range) backward fraction was 12% (3–24%) and it was >20% in 21 patients. Maximum backflow occurred at near 90% of the cardiac cycle, coinciding with atrial contraction. The backward fraction was associated with maximal right atrial pressure (Spearman's r=0.77), right ventricular end-diastolic stiffness (r=0.65) and right ventricular end-diastolic pressure (r=0.77), and was negatively associated with stroke volume (r= –0.61) (all pSignificant backward flow in the vena cava was observed in a large group of PAH patients and occurred mostly during atrial contraction as a consequence of impaired right ventricular filling due to right ventricular diastolic stiffness. The backward flow due to tricuspid regurgitation was of significance in only a small minority of patients.

Rationale: Multiple mechanisms have been discovered underlying the pathogenesis of pulmonary arterial hypertension (PAH), including reactive oxygen species (ROS), inflammation and reduced bone morphogenic protein receptor (BMPR)2. MnTBAP can mimic the effects of manganese-superoxide dismutase to reduce ROS. Moreover, MnTBAP can reduce inflammation in endothelial cells via up-regulation of BMPR2. Collectively, we hypothesized that MnTBAP can be used to treat PAH. Methods: Experimental PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 followed by 4-weeks hypoxia and 2-weeks normoxia. At week 6, animals were randomized to receive either saline or MnTBAP until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10. Heart and lung tissues were collected. Results: MnTBAP reduced RV afterload and total pulmonary resistance in SuHx rats. Moreover, MnTBAP improved RV function by increasing stroke volume and TAPSE, as well as reducing RV end diastolic diameter and stiffness. Further tissue analysis by histology revealed that MnTBAP reduced pulmonary vascular remodeling by reducing both intima and media layer thickness. Conclusion: MnTBAP treatment can partly reverse RV afterload and pulmonary vascular remodeling in established experimental PAH. Together with the improved cardiac function, MnTBAP may be a promising intervention for PAH.

While exercise capacity is reduced in all forms of pulmonary hypertension, only in idiopathic pulmonary arterial hypertension (iPAH) this is known to be related to right ventricular (RV) -arterial uncoupling. Here we compare RV-arterial coupling (RVAC) during exercise between patients with chronic thromboembolic pulmonary hypertension (CTEPH) and iPAH. We prospectively included 12 CTEPH and 12 iPAH patients who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and January 2019. RV contractility, defined as end-systolic elestance (Ees), and RV afterload (Ea) were assessed both at rest and during exercise by using single beat pressure-volume loop analysis. RVAC was calculated as Ees/Ea. RV afterload and contractility were similar at rest in iPAH and CTEPH (figure 1). In both groups, Ea significantly increased during exercise, while RV contractility did not change. Resting RVAC was higher in iPAH than in CPTEH (1,6 (0,6) vs. 1,2 (0,3); p CTEPH patients have a worse RV phenotype at rest compared to iPAH patients. Both groups fail to increase contractility during exercise.

PURPOSE OF REVIEW: Right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although substantial progress has been made in understanding the development of RV failure in the last decennia, this has not yet resulted in the development of RV selective therapies. In this review, we will discuss the current status on the treatment of RV failure and potential novel therapeutic strategies that are currently being investigated in clinical trials.RECENT FINDINGS: Increased afterload results in elevated wall tension. Consequences of increased wall tension include autonomic disbalance, metabolic shift and inflammation, negatively affecting RV contractility. Compromised RV systolic function and low cardiac output activate renin-angiotensin aldosterone system, which leads to fluid retention and further increase in RV wall tension. This vicious circle can be interrupted by directly targeting the determinants of RV wall tension; preload and afterload by PAH-medications and diuretics, but is also possibly by restoring neurohormonal and metabolic disbalance, and inhibiting maladaptive inflammation. A variety of RV selective drugs are currently being studied in clinical trials.SUMMARY: Nowadays, afterload reduction is still the cornerstone in treatment of PAH. New treatments targeting important pathobiological determinants of RV failure directly are emerging.

Cardiac fibrosis contributes to the development of heart failure in pulmonary hypertension. We aimed to assess the development of fibrosis and the effects of treatment with the anti-fibrotic agent pirfenidone in pressure overload induced right ventricular (RV) failure. Wistar rat weanlings were randomized to pulmonary trunk banding (PTB) or sham surgery. One week after the procedure, PTB rats were randomized into two groups with either six weeks on standard chow or treatment with pirfenidone mixed in chow (700 mg/kg/day). RV hemodynamic effects were evaluated by echocardiography, cardiac magnetic resonance imaging (MRI), and pressure-volume measurements. Sections from the isolated RV, left ventricle, and septum were sampled systematically; stereological point grids and the nucleator were used to estimate volume of fibrosis and cardiac hypertrophy, respectively. PTB caused RV failure in all rats subjected to the procedure. The volume fraction of fibrosis in the RV increased threefold in PTB rats corresponding to a sixfold increase in total volume of RV fibrosis. Volume fraction of fibrosis and total volume of fibrosis also increased in the septum and in the left ventricle. Pirfenidone reduced body weight but did not improve RV hemodynamics or reduce cardiac fibrosis. RV cardiomyocyte profile area was increased twofold in PTB rats without any effect of pirfenidone. RV pressure overload after PTB induced not only RV but also septal and left ventricular fibrosis assessed by stereology. Treatment with pirfenidone reduced body weight but did not reduce the development of cardiac fibrosis or delay the progression of RV failure.

Visual Abstract, Highlights • Neurohormonal dysfunction (increased sympathetic nervous system and renin angiotensin-aldosterone system) play an important role in pulmonary hypertension progression. • In this proof-of-concept study we demonstrated in 2 pulmonary hypertension rat models that renal denervation therapy improved pulmonary vascular remodeling, lowered right ventricular afterload, and decreased right ventricular stiffness. • Renal denervation effects may be associated with a suppression of the renin-angiotensin-aldosterone system., Summary Neurohormonal overactivation plays an important role in pulmonary hypertension (PH). In this context, renal denervation, which aims to inhibit the neurohormonal systems, may be a promising adjunct therapy in PH. In this proof-of-concept study, we have demonstrated in 2 experimental models of PH that renal denervation delayed disease progression, reduced pulmonary vascular remodeling, lowered right ventricular afterload, and decreased right ventricular diastolic stiffness, most likely by suppression of the renin-angiotensin-aldosterone system.

While beta-blockers are considered contraindicated in pulmonary arterial hypertension (PAH), the prognostic significance of sympathetic nervous system over-activity suggests a potential benefit of beta-blocker therapy. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol on right ventricular ejection fraction (RVEF) in idiopathic PAH (iPAH) patients. Additional efficacy and safety parameters were explored.Patients with optimally treated, stable iPAH (New York Heart Association functional class II/III) were randomised to placebo or bisoprolol. Imaging and functional measurements were performed at baseline, crossover and end of study.18 iPAH patients were included, because inclusion faltered before enrolment of the targeted 25 patients. 17 patients completed 6 months of bisoprolol, 15 tolerated bisoprolol, one patient required intravenous diuretics. Bisoprolol was associated with a lower heart rate (17 beats per minute, p=0.0001) but RVEF remained unchanged. A drop in cardiac index (0.5 L·min−1·m−2, p=0.015) was observed, along with a trend towards a decreased 6-min walking distance (6MWD).Although careful up-titration of bisoprolol was tolerated by most patients and resulted in a decreased heart rate, no benefit of bisoprolol in iPAH was demonstrated. Decreases in cardiac index and 6MWD suggest a deteriorated cardiac function. The results do not favour the use of bisoprolol in iPAH patients.

Patients with pulmonary hypertension (PH) suffer from inspiratory muscle weakness. However, the pathophysiology of inspiratory muscle dysfunction in PH is unknown. We hypothesized that weakness of the diaphragm, the main inspiratory muscle, is an important contributor to inspiratory muscle dysfunction in PH patients. Our objective was to combine ex vivo diaphragm muscle fiber contractility measurements with measures of in vivo inspiratory muscle function in chronic thromboembolic pulmonary hypertension (CTEPH) patients. To assess diaphragm muscle contractility, function was studied in vivo by maximum inspiratory pressure (MIP) and ex vivo in diaphragm biopsies of the same CTEPH patients ( N = 13) obtained during pulmonary endarterectomy. Patients undergoing elective lung surgery served as controls ( N = 15). Muscle fiber cross-sectional area (CSA) was determined in cryosections and contractility in permeabilized muscle fibers. Diaphragm muscle fiber CSA was not significantly different between control and CTEPH patients in both slow-twitch and fast-twitch fibers. Maximal force-generating capacity was significantly lower in slow-twitch muscle fibers of CTEPH patients, whereas no difference was observed in fast-twitch muscle fibers. The maximal force of diaphragm muscle fibers correlated significantly with MIP. The calcium sensitivity of force generation was significantly reduced in fast-twitch muscle fibers of CTEPH patients, resulting in a ∼40% reduction of submaximal force generation. The fast skeletal troponin activator CK-2066260 (5 μM) restored submaximal force generation to levels exceeding those observed in control subjects. In conclusion, diaphragm muscle fiber contractility is hampered in CTEPH patients and contributes to the reduced function of the inspiratory muscles in CTEPH patients.

Pulmonary hypertension is a fatal condition of elevated pulmonary pressures, complicated by right heart failure. Pulmonary hypertension appears in various forms; one of those is pulmonary arterial hypertension (PAH) and is particularly characterised by progressive remodelling and obstruction of the smaller pulmonary vessels. Neurohormonal imbalance in PAH patients is associated with worse prognosis and survival. In this back-to-basics article on neurohormonal modulation in PAH, we provide an overview of the pharmacological and nonpharmacological strategies that have been tested pre-clinically and clinically. The benefit of neurohormonal modulation strategies in PAH patients has been limited by lack of insight into how the neurohormonal system is changed throughout the disease and difficulties in translation from animal models to human trials. We propose that longitudinal and individual assessments of neurohormonal status are required to improve the timing and specificity of neurohormonal modulation strategies. Ongoing developments in imaging techniques such as positron emission tomography may become helpful to determine neurohormonal status in PAH patients in different disease stages and optimise individual treatment responses., Better insight into neurohormonal changes throughout the development of pulmonary arterial hypertension and associated right heart failure is needed to allow efficacious intervention http://bit.ly/2NCV0nO

The role of right ventricular (RV) fibrosis in pulmonary hypertension (PH) remains a subject of ongoing discussion. Alterations of the collagen network of the extracellular matrix may help prevent ventricular dilatation in the pressure-overloaded RV. At the same time, fibrosis impairs cardiac function, and a growing body of experimental data suggests that fibrosis plays a crucial role in the development of RV failure. In idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, the RV is exposed to a ≈5 times increased afterload, which makes these conditions excellent models for studying the impact of pressure overload on RV structure. With this review, we present clinical evidence of RV fibrosis in idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, explore the correlation between fibrosis and RV function, and discuss the clinical relevance of RV fibrosis in patients with PH. We postulate that RV fibrosis has a dual role in patients with pressure-overloaded RVs of idiopathic pulmonary arterial hypertension and chronic thromboembolic PH: as part of an adaptive response to prevent cardiomyocyte overstretch and to maintain RV shape for optimal function, and as part of a maladaptive response that increases diastolic stiffness, perturbs cardiomyocyte excitation-contraction coupling, and disrupts the coordination of myocardial contraction. Finally, we discuss potential novel therapeutic strategies and describe more sensitive techniques to quantify RV fibrosis, which may be used to clarify the causal relation between RV fibrosis and RV function in future research.

BACKGROUND: Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB).METHODS: Male Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses.RESULTS: PTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats.CONCLUSION: Treatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle.

Background: Reactive oxygen species (ROS) play a crucial role in the pathogenesis of pulmonary arterial hypertension (PAH). Monoamine oxidases (MAO), a class of enzymes located in the outer mitochondrial membrane, are important ROS sources. Increased MAO-A expression in endothelial cells and cardiomyocytes was found to contribute to vascular dysfunction and left heart failure. MAO-A inhibition can improve vascular dysfunction and heart failure. Collectively, given the effects of MAO-A on both vascular and cardiac function, we hypothesized that inhibition of MAO-A can be used to treat PAH. Methods: PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 (25 mg/kg) followed by 4-weeks exposure to hypoxia and 2-weeks of normoxia. At week 8, animals were randomized to receive either intraperitoneal injection of saline or the MAO-A inhibitor clorgyline 10 mg/kg, followed by 2 mg/kg every 3 days until week 10. Echocardiography and RV catheterization was performed at week 10 and heart and lung tissues were collected for further analysis. Results: Compared to the vehicle group, clorgyline treatment reduced right ventricular (RV) systolic pressure and RV afterload. Moreover, clorgyline improved RV function by reducing RV hypertrophy and stiffness. Further tissue analysis by histology revealed that clorgyline reduced pulmonary vascular remodeling by reducing intima layer thickness. Conclusion: Clorgyline partly reversed RV systolic pressure and RV afterload in established experimental PAH. Together with the observed reduced RV remodeling, MAO-A inhibition may be a promising intervention for PAH.

Background: Gender is known to play a role in right ventricular (RV) adaption in pulmonary arterial hypertension (PAH). Sex hormone levels change with aging both in males and females. However effect of aging on RV function within sexes has not been explored. Aim: To study the effect of age on PAH disease severity and RV adaptation in both sexes. Methods: Systolic elastance (Ees), arterial elastance (Ea), diastolic elastance (Eed) and RV-arterial coupling (Ees/Ea) were determined in 88 newly diagnosed, treatment naive, idiopathic and hereditary PAH patients using the single-beat pressure volume analysis. Right ventricular ejection fraction (RVEF) was determined by CMR. Both males and females were divided in an age ≤50 and age > 50 years group, as 50 years is the mean age women reach the menopause. Results: Results are presented in figure 1. Ees (p=0.56), Ea (p=0.40), Ees/Ea (p=0.87) or Eed (p=0.67) were not related to age in women. However, young men presented with a higher afterload (p =0.0006) when compared to men>50 years old. In addition, baseline RVEF was lower in young men compared to men>50 years (21%±11.7 vs. 35%±12.4, p=0.0431). Conclusion: Young males with PAH presented with a high afterload and low RVEF. Further research in a larger cohort is warranted to elucidate whether this is a consequence of a distinct disease phenotype.

In pulmonary arterial hypertension, afterload on the right ventricle is increased. Due to several adaptive mechanisms, the right ventricle is able to cope with a three- to fivefold increase in afterload. However, when adaptive mechanisms are no longer sufficient to compensate for this increase, the patient will develop right ventricular dysfunction and failure. This chapter provides an overview of mechanisms currently considered as having important roles in right ventricular adaptation and right ventricular failure.

Exercise tolerance is decreased in patients with pulmonary hypertension (PH). It is unknown whether exercise intolerance in PH coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility.To investigate in patients with PH the RV exertional contractile reserve, defined as the rest-to-exercise response in end-systolic elastance (ΔEes), and the effects of exercise on the matching of Ees and RV afterload (Ea) (i.e., RV-arterial coupling; Ees/Ea). In addition, we compared ΔEes with a recently proposed surrogate, the rest-to-exercise change in pulmonary artery pressure (ΔPAP).We prospectively included 17 patients with precapillary PH and 7 control subjects without PH who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and July 2014. Ees and Ees/Ea were assessed using single-beat pressure-volume loop analysis.Exercise data in 16 patients with PH and 5 control subjects were of sufficient quality for analysis. Ees significantly increased from rest to exercise in control subjects but not in patients with PH. Ea significantly increased in both groups. As a result, exercise led to a decrease in Ees/Ea in patients with PH, whereas Ees/Ea was unaffected in control subjects (Pinteraction = 0.009). In patients with PH, ΔPAP was not related to ΔEes but significantly correlated to the rest-to-exercise change in heart rate.In contrast to control subjects, patients with PH were unable to increase Ees during submaximal exercise. Failure to compensate for the further increase in Ea during exercise led to deterioration in Ees/Ea. Furthermore, ΔPAP did not reflect ΔEes but rather the change in heart rate.

Right heart failure may develop from pulmonary arterial hypertension or various forms of congenital heart disease. Right ventricular adaptation to the increased afterload is the most important prognostic factor in pulmonary hypertension and congenital heart disease, which share important pathophysiological mechanisms, despite having different aetiologies. There is substantial evidence of increased sympathetic nervous system activation in right heart failure related to both pulmonary hypertension and congenital heart disease. It is unknown to which degree this activation is an adaptive response, a maladaptive response, or if it mainly reflects disease progression. Several experimental studies and clinical trials have been conducted to answer these questions. Here, we review the existing knowledge on sympathetic nervous system activation and the effects of β-adrenoceptor blockade in experimental and clinical right heart failure. This review identifies important gaps in our understanding of the right ventricle and discusses the potential of β-blockers in the treatment of right heart failure.

Background: Inflammation plays a crucial role in the pathogenesis of pulmonary arterial hypertension (PAH), partly by stimulating proliferation of pulmonary arterial smooth muscle cells (SMC) and endothelial cells (EC). 6-Mercaptopurine (6-MP) is an immunosuppressive drug used to treat various autoimmune and chronic inflammatory diseases. Recently, we and others have shown that 6-MP not only inhibits macrophage and T cell activation, but also reduces the proliferation of SMC and EC as well as the inflammatory response of EC. Collectively, given the effects of 6-MP on inflammation, SMC and EC, we hypothesized that 6-MP may become a promising treatment of PAH. Methods: PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 (25 mg/kg) followed by 4-week exposure to hypoxia and 2-week normoxia. At week 6, animals were randomized into vehicle or 6-MP treatment group, by receiving vehicle (DMSO) or 6-MP (7.5 mg/kg/day) in water until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10, after which they were exsanguinated. Both heart and lung tissues were collected for further analysis. Results: Compared to the vehicle group, 6-MP reduced RV systolic pressure, RV afterload and total pulmonary resistance. Moreover, 6-MP improved cardiac function by reducing RV stiffness, and increasing stroke volume and cardiac output. In addition, it partly reversed RV remodeling by reducing RV fibrosis. Conclusion: 6-MP partly reversed RV systolic pressure and RV afterload in established PAH. Together with the observed improved RV remodeling and cardiac function, 6-MP may be a promising intervention for PAH.

A recent study clearly demonstrates that right ventricular (RV) hypertrophy is a prognostic marker of pulmonary arterial hypertension, triggering us to rethink the concept of RV hypertrophyhttp://ow.ly/vD0e30nHvFm

Background Sympathetic adrenergic stimulation and the renin-angiotensin-aldosterone system are highly elevated in right heart failure. We evaluated if treatment with the adrenergic receptor blocker bisoprolol or the angiotensin II receptor blocker losartan could prevent the progression of right ventricular (RV) hypertrophy and failure in rats after pulmonary trunk banding (PTB). Methods and Results Male Wistar rats were randomized to severe PTB with a 0.5-mm banding clip (PTB0.5, n = 29), moderate PTB with a 0.6-mm banding clip (PTB0.6, n = 28), or sham operation (SHAM, n = 13). The PTB0.5 and PTB0.6 rats were randomized to 6 weeks of 10 mg/kg/d bisoprolol treatment, 20 mg/kg/d losartan treatment, or vehicle treatment. The PTB caused hypertrophy, dilation, and reduced function of the RV in all rats subjected to the procedure. Rats subjected to the more severe banding developed decompensated RV failure with extracardiac manifestations. Treatment with bisoprolol slowed the heart rate, and treatment with losartan lowered mean arterial pressure, confirming adequate dosing, but none of the treatments improved RV function or arrested the progression of RV hypertrophy and failure compared with vehicle. Conclusions In our PTB model of pressure overload–induced RV hypertrophy and failure, treatment with bisoprolol and losartan did not demonstrate any beneficial effects in compensated or decompensated RV failure.

BACKGROUND: After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function. OBJECTIVES: The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients. METHODS: LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated. RESULTS: Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (∼30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (∼25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ∼30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation. CONCLUSIONS: The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients. © 2014 by the American College of Cardiology Foundation.

In pulmonary arterial hypertension (PAH), right ventricular (RV) adaptation is essential to overcome the chronic increases in RV pressure overload. Ultimately, RV compensatory mechanisms are not sufficient and patients succumb to RV failure. The processes underlying the transition of RV adaptation to RV failure are not well understood. In this review, we propose that important insights in RV adaptation processes can be obtained by comparing different etiologies of PAH, namely patients with PAH secondary to Eisenmenger syndrome, patients with PAH secondary to systemic sclerosis and patients where no cause is identified: idiopathic PAH. Although the amount of RV afterload does not differ between these patient groups, their prognosis is distinctly different. We will show that an adaptive RV phenotype, as is observed in Eisenmenger patients, coincides with RV hypertrophy, increased RV contractility, low RV fibrosis and low RV diastolic stiffness. Whereas a phenotype of RV failure, as is observed in patients with PAH-secondary to systemic sclerosis, is characterized by impaired contractile reserve, RV fibrosis and RV diastolic stiffness.

Background— The role of right ventricular (RV) diastolic stiffness in pulmonary arterial hypertension (PAH) is not well established. Therefore, we investigated the presence and possible underlying mechanisms of RV diastolic stiffness in PAH patients. Methods and Results— Single-beat RV pressure-volume analyses were performed in 21 PAH patients and 7 control subjects to study RV diastolic stiffness. Data are presented as mean±SEM. RV diastolic stiffness (β) was significantly increased in PAH patients (PAH, 0.050±0.005 versus control, 0.029±0.003; P 2 versus control, 218±21 μm 2 ; P P 200%; P interaction P Conclusions— RV diastolic stiffness is significantly increased in PAH patients, with important contributions from increased collagen and intrinsic stiffening of the RV cardiomyocyte sarcomeres.

International audience; Contrasting with the major attention that left heart failure has received, right heart failure remains understudied both at the preclinical and clinical levels. However, right ventricle failure is a major predictor of outcomes in patients with precapillary pulmonary hypertension because of pulmonary arterial hypertension, and in patients with postcapillary pulmonary hypertension because of left heart disease. In pulmonary hypertension, the status of the right ventricle is one of the most important predictors of both morbidity and mortality. Paradoxically, there are currently no approved therapies targeting the right ventricle in pulmonary hypertension. By analogy with the key role of β-blockers in the management of left heart failure, some authors have proposed to use these agents to support the right ventricle function in pulmonary hypertension. In this review, we summarize the current knowledge on the use of β-blockers in pulmonary hypertension.

Pulmonary hypertension (PH) resulting from left heart failure is an increasingly recognized clinical entity. To distinguish isolated postcapillary PH from combined post‐ and precapillary PH, the use of a diastolic pressure gradient (DPG = diastolic Pulmonary Artery Pressure − Pulmonary Arterial Wedge Pressure, dPAP − PAWP) has been advocated over the transpulmonary pressure gradient (TPG = mean Pulmonary Artery Pressure − PAWP, mPAP − PAWP) since DPG was suggested to be independent of cardiac output (CO) and only slightly related to PAWP, while TPG depends on both. We quantitatively derived and compared the DPG and TPG. Using right heart catheterization data (n = 1054), we determined systolic pulmonary artery pressure (sPAP), dPAP and mPAP, PAWP, and CO. From this data, we derived TPG and DPG and tested their dependence on PAWP and CO. We found that dPAP and sPAP are proportional with mPAP over a wide range of PAWP (1–31 mmHg), with dPAP = 0.62mPAP and sPAP = 1.61mPAP. As a consequence, TPG and DPG are equally dependent on PAWP: TPG = mPAP − PAWP, and DPG = 0.62mPAP − PAWP. Furthermore, we showed that both TPG and DPG depend on CO. The absolute increase in DPG with CO is 62% of the TPG increase with CO, but the relative dependence is the same. Both TPG and DPG depend on PAWP and CO. Thus, in principle, there are no major advantages for using DPG to distinguish postcapillary pulmonary hypertension from combined post‐ and precapillary pulmonary hypertension.

Background— The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction. Methods and Results— By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction. Conclusions— RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness.

Patients with idiopathic pulmonary arterial hypertension (IPAH) and a reduced diffusion capacity of the lung for carbon monoxide (DLCO) have a worse survival compared to IPAH patients with a preserved DLCO. Whether this poor survival can be explained by unresponsiveness to pulmonary hypertension (PH)-specific vasodilatory therapy is unknown. Therefore, the aim of this study was to evaluate the hemodynamic and cardiac response to PH-specific vasodilatory therapy in patients with IPAH and a reduced DLCO. Retrospectively, we studied treatment naı¨ve hereditary and IPAH patients diagnosed between January 1990 and May 2015 at the VU University Medical Center. After exclusion of participants without available baseline DLCO measurement or right heart catheterization data and participants carrying a BMPR2 mutation, 166 participants could be included in this study. Subsequently, hemodynamics, cardiac function, exercise capacity, and oxygenation at baseline and after PH-specific vasodilatory therapy were compared between IPAH patients with a preserved DLCO (DLCO >62%), IPAH patients with a moderately reduced DLCO (DLCO 43–62%), and IPAH patients with a severely reduced DLCO (DLCO

Heart failure with preserved ejection fraction (HFpEF) is a growing healthcare burden worldwide and its prevalence is increasing. Diagnosing HFpEF is challenging and relies upon the presence of symptoms and/or signs of heart failure, preserved left ventricular systolic function, and evidence of diastolic dysfunction. Current diagnostic algorithms mainly rely on echocardiography (E/e’) and biomarkers (NT-proBNP). However, only a minority of patients with HFpEF are identified, and especially HFpEF patients at an early stage of the disease are easily missed. We propose to incorporate invasive stress testing, by means of right heart catheterisation at rest and during exercise, and accurate assessment of right ventricular function, by means of cardiac magnetic resonance imaging. These additions to the current diagnostic work-up will improve diagnostic sensitivity and accurate staging of HFpEF patients.